Objective:To assess the preliminary efficacy and safety of modified Société Internationale d′Oncologie Pédiatrique Epithelial Liver Tumor Study Group (SIOPEL)-4 protocol for pediatric hepatoblastoma (HB) with lung metastases.Methods:This prospective cohort study enrolled 27 newly diagnosed pediatric HB with lung metastases who received the modified SIOPEL-4 protocol at Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children′s Hospital between January 2020 to December 2023. Clinical characteristics, lung response rates to induction chemotherapy, treatment outcomes, prognostic factors and sever chemotherapy toxicities at different stages were analyzed. Survival analysis was performed by Kaplan-Meier method. Univariate prognostic analysis was conducted by Log-Rank test.Results:Of the 27 patients, there were 17 males and 10 females, with the age of 21 (15, 33) months. During the follow-up of 31 (12, 45) months for 17 continuous complete remission patients, 4 cases disease progression (2 cases death) and 6 cases relapse were observed. The 2-year event free survival (EFS) and overall survival (OS) rate was (58±11)% and (89±7)%, respectively. All the 27 patients had response to block 1-3 induction chemotherapy (cisplatin+doxorubicin), with 14 cases (52%) achieving complete response and 13 cases (48%) achieving partial response of lung metastatic lesions, the 2-year EFS rate was (81±12)% and (34±14)%, respectively ( χ 2=6.76, P=0.009), the 2-year OS rate was 100% and (79±13)%, respectively ( χ2=2.12, P=0.145). Patients with caudate lobe tumors or ≥10 pulmonary metastatic nodules had significantly lower EFS rates ( χ2=5.36, 7.84, P=0.021, 0.005, respectively). The incidence of grade 3/4 neutropenia after block 1-3 induction chemotherapy, CD (carboplatin+doxorubicin), and VI (vincristine+irinotecan) consolidation chemotherapy was 90% (73/81), 75% (58/77), and 31% (11/35), respectively. The incidence of grade 3/4 thrombocytopenia was 77% (62/81), 69% (53/77), and 14% (5/35), respectively. The incidence of grade 3/4 infections was 64% (52/81), 25% (19/77), and 20% (7/35), respectively. The differences between the groups were statistically significant ( χ2=43.51, 42.69, 33.00, all P<0.001). Two patients (10%) of the 20 evaluable patients for ototoxicity occurred grade 3 and higher hearing impairment, with 1 patient requiring a hearing aid. Conclusions:The modified SIOPEL-4 regimen shows good preliminary efficacy and safety in treating pediatric HB with lung metastases. The prognosis for patients with residual lesions in the lungs after induction chemotherapy needs to be improved. Attention should be given to the ototoxicity induced by high-dose cisplatin chemotherapy.

Objective:To assess the preliminary efficacy and safety of modified Société Internationale d′Oncologie Pédiatrique Epithelial Liver Tumor Study Group (SIOPEL)-4 protocol for pediatric hepatoblastoma (HB) with lung metastases.Methods:This prospective cohort study enrolled 27 newly diagnosed pediatric HB with lung metastases who received the modified SIOPEL-4 protocol at Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children′s Hospital between January 2020 to December 2023. Clinical characteristics, lung response rates to induction chemotherapy, treatment outcomes, prognostic factors and sever chemotherapy toxicities at different stages were analyzed. Survival analysis was performed by Kaplan-Meier method. Univariate prognostic analysis was conducted by Log-Rank test.Results:Of the 27 patients, there were 17 males and 10 females, with the age of 21 (15, 33) months. During the follow-up of 31 (12, 45) months for 17 continuous complete remission patients, 4 cases disease progression (2 cases death) and 6 cases relapse were observed. The 2-year event free survival (EFS) and overall survival (OS) rate was (58±11)% and (89±7)%, respectively. All the 27 patients had response to block 1-3 induction chemotherapy (cisplatin+doxorubicin), with 14 cases (52%) achieving complete response and 13 cases (48%) achieving partial response of lung metastatic lesions, the 2-year EFS rate was (81±12)% and (34±14)%, respectively ( χ 2=6.76, P=0.009), the 2-year OS rate was 100% and (79±13)%, respectively ( χ2=2.12, P=0.145). Patients with caudate lobe tumors or ≥10 pulmonary metastatic nodules had significantly lower EFS rates ( χ2=5.36, 7.84, P=0.021, 0.005, respectively). The incidence of grade 3/4 neutropenia after block 1-3 induction chemotherapy, CD (carboplatin+doxorubicin), and VI (vincristine+irinotecan) consolidation chemotherapy was 90% (73/81), 75% (58/77), and 31% (11/35), respectively. The incidence of grade 3/4 thrombocytopenia was 77% (62/81), 69% (53/77), and 14% (5/35), respectively. The incidence of grade 3/4 infections was 64% (52/81), 25% (19/77), and 20% (7/35), respectively. The differences between the groups were statistically significant ( χ2=43.51, 42.69, 33.00, all P<0.001). Two patients (10%) of the 20 evaluable patients for ototoxicity occurred grade 3 and higher hearing impairment, with 1 patient requiring a hearing aid. Conclusions:The modified SIOPEL-4 regimen shows good preliminary efficacy and safety in treating pediatric HB with lung metastases. The prognosis for patients with residual lesions in the lungs after induction chemotherapy needs to be improved. Attention should be given to the ototoxicity induced by high-dose cisplatin chemotherapy.

Introduction::Observational studies have revealed an association between waist circumference (WC) and atrial fibrillation (AF). However, it is difficult to infer a causal relationship from observational studies because the observed associations could be confounded by unknown risk factors. Therefore, the causal role of WC in AF is unclear. This study was designed to investigate the causal association between WC and AF using a two-sample Mendelian randomization (MR) analysis.Methods::In our two-sample MR analysis, the genetic variation used as an instrumental variable for MR was acquired from a genome-wide association study (GWAS) of WC (42 single nucleotide polymorphisms with a genetic significance of P <5 × 10 –8). The data of WC (from the Genetic Investigation of ANthropometric Traits consortium, containing 232,101 participants) and the data of AF (from the European Bioinformatics Institute database, containing 55,114 AF cases and 482,295 controls) were used to assess the causal role of WC on AF. Three different approaches (inverse variance weighted [IVW], MR–Egger, and weighted median regression) were used to ensure that our results more reliable. Results::All three MR analyses provided evidence of a positive causal association between high WC and AF. High WC was suggested to increase the risk of AF based on the IVW method (odds ratio [OR] = 1.43, 95% confidence interval [CI], 1.30–1.58, P = 2.51 × 10 -13). The results of MR–Egger and weighted median regression exhibited similar trends (MR–Egger OR = 1.40 [95% CI, 1.08–1.81], P = 1.61 × 10 -2; weighted median OR = 1.39 [95% CI, 1.21–1.61], P = 1.62 × 10 -6). MR–Egger intercepts and funnel plots showed no directional pleiotropic effects between high WC and AF. Conclusions::Our findings suggest that greater WC is associated with an increased risk of AF. Taking measures to reduce WC may help prevent the occurrence of AF.

Pyroptosis is a novel mode for programmed cell death discovered and confirmed in recent years. The Gasdermins (GSDMs) family is a key effector molecule mediating pyroptosis. As an important cause of extensive inflammatory damage and side effects of conventional chemotherapy drugs, anomalous pyroptosis has also been associated with hearing loss, tumor, and disorders of the immune system. The GSDME protein, encoded by the GSDME ( DFNA5) gene, belongs to the GSDMs family and is a key factor mediating pyroptosis. Gain-of-function variants of the GSDME gene can lead to GSDME-related hearing loss, which shows an autosomal dominant inheritance. This article has reviewed the role of GSDME-mediated pyroptosis in the pathogenesis of GSDME-related hearing loss, with an aim to provide insights into the treatment of GSDME-related hearing loss.

OBJECTIVE To investigate the anti-pulmonary fibrosis effect of linarin in vivo and in vitro， and investigate its mechanism preliminarily. METHODS C57BL/6J mice were randomly divided into normal group （carboxymethylcellulose sodium）， model group （carboxymethylcellulose sodium）， positive control group （pirfenidone， 200 mg/kg）， linarin low-dose and high-dose groups （12.5， 25 mg/kg）， with 8 mice in each group. Except for normal group， pulmonary fibrosis model was induced in other groups. After modeling， they were given relevant medicine intragastrically， once a day， for consecutive 14 d. The general situation of mice was observed， and their lung indexes were measured； the levels of tumor necrosis factor-α （TNF-α） and transforming growth factor-β1（ TGF-β1） in serum and interleukin-6 （IL-6） in lung tissue were determined. Hematoxylin-eosin （HE） staining and Masson staining were used to observe the histopathological morphology of lung. The pulmonary fibrosis was scored according to Ashcroft score standard. The expressions of α-smooth muscle actin （α-SMA） and （type Ⅰ collagen， Collagen Ⅰ）， phosphorylated extracellular signal-regulated kinase （p-ERK1/2） and TGF-β1 in lung tissues were detected. HFL1 cells were stimulated by TGF- β1 to form pulmonary fibrosis model in vitro， which were divided into normal group， model group and linarin low-， medium- and high-concentration groups （3.7， 7.4， 14.8 mg/L）. After being cultured for 48 h， the protein expressions of α-SMA， Collagen Ⅰ and p-ERK1/2 in HFL1 cells were detected. RESULTS In vivo， compared with normal group， the lung index of model group and the levels of TNF- α， TGF- β1 and IL-6 were significantly increased （P＜0.01）. There were a large number of inflammatory infiltration and cellular fibrosis lesions in the alveoli， and a large number of collagen depositions. The scores of HE staining and Masson staining were significantly increased （P＜0.01）. The protein expressions of α-SMA， Collagen Ⅰ， p-ERK1/2 and TGF-β1 in lung tissue were up-regulated significantly （P＜0.01）. Compared with model group， above indexes of mice were improved significantly in linarin high-dose group （P＜0.05 or P＜0.01）， and most of indexes （except for lung index） were improved significantly in linarin low-dose group （P＜0.05 or P＜0.01）. In vitro， compared with blank group， the density of cells in the model group increased， and obvious proliferation and other changes occurred； protein expressions of α-SMA， Collagen Ⅰ and p-ERK1/2 were significantly up-regulated （P＜0.05 or P＜0.01）. Compared with model group， the cell density of each concentration group was decreased and the morphology gradually returned to normal； the expressions of above proteins in linarin high-concentration group and the protein expression of p-ERK1/2 in linarin medium-concentration group were down-regulated significantly（P＜0.05 or P＜0.01）. CONCLUSIONS Linarin may regulate ERK and inflammatory pathways to reduce the inflammatory response， thereby exerting anti-pulmonary fibrosis effect.

Pulmonary fibrosis is the end-stage manifestation of a large class of lung diseases characterized by fibroblast proliferation and accumulation of a large amount of extracellular matrix accompanied by inflammatory injury and tissue structure destruction. Studies have shown that flavonoids have anti-pulmonary fibrosis effects through multiple paths， including dihydromyricetin， morin and fisetin can inhibit fibroblast differentiation； Trollius altaicus flavonoids， hesperidin and linarin can play an anti-inflammatory role； total flavonoids from Scutellaria baicalensis， scutellarin and chrysin can inhibit epithelial- mesenchymal transition； total flavonoids of Litchi chinensis， diosmin and silybin can play an anti-oxidative stress role； quercetin， baicalin and apigenin can regulate autophagy； total flavonoids of Oxytropis falcata， calycosin and dihydroquercetin can regulate apoptosis； naringin， scutellarin and total flavonoids of Dracocephalum moldavica can inhibit pyroptosis， thus exerting anti- pulmonary fibrosis effects.

Objective:To evaluate the predictive value of the serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration for postoperative acute kidney injury (AKI) in neonates undergoing cardiac surgery.Methods:Perioperative data of 110 consecutive neonates (≤28 days) who underwent cardiac surgery in our hospital from October 2017 to May 2021, were collected retrospectively.According to pROCK criteria, the patients were divided into AKI group and non-AKI group.Demographics, predominant diagnosis, laboratory examination, perioperative management and postoperative outcomes were compared between two groups.The concentration of serum NT-proBNP was routinely measured within 12 h after operation.Multivariate logistic regression analysis was performed for the association between serum NT-proBNP and postoperative AKI.Receiver operating characteristic curve was drawn, and the predictive value of serum NT-proBNP for postoperative AKI was determined according to the area under the curve.Results:A total of 106 neonates were enrolled, and the incidence of postoperative AKI was 54.7%.There were significant difference in the baseline hemoglobin concentration, hematocrit and serum creatinine and serum NT-proBNP concentration between AKI group and non-AKI group ( P<0.05). Multivariate logistic regression analysis indicated that NT-proBNP level was an independent risk factor for AKI after cardiac surgery in neonates ( odds ratio 2.49, 95% confidence interval 1.183-5.23, P=0.016). The area under the curve of NT-proBNP predicting AKI after cardiac surgery was 0.66 (95% confidence interval 0.56-0.76, P=0.007). Conclusions:Elevated serum NT-proBNP concentration is an independent risk factor for AKI after cardiac surgery in neonates and has a certain predictive value for AKI, and close monitoring of perioperative NT-proBNP level is helpful for early identification of high-risk neonates.

Objective:To investigate the clinical efficacy and safety of polymyxin B in the treatment of sepsis caused by extensively-drug resistant (XDR) Gram-negative bacteria.Methods:A retrospective analysis of 39 septic patients with XDR Gram-negative bacterial infection treated with polymyxin B in the department of critical care medicine of Xiangya Hospital of Central South University from June 2018 to September 2019 were enrolled. The clinical characteristics, bacterial culture, the sensitivity antibacterial drugs, types and courses of antibiotics, biochemical indexes, and acute physiology and chronic health evaluationⅡ(APACHEⅡ) before and after polymyxin B treatment were collected, to assess microbial clearance and efficacy, drug related adverse effects, and 28-day mortality in septic patients with XDR.Results:Of the 39 septic patients with XDR, 32 (82.1%) were male, with the mean age of (53.6±12.6) years old. The main infection site was pulmonary infection (51.2%), and the treatment courses of polymyxin B were ≥ 5 days. A total of 66 pathogenic bacteria were detected from 39 patients. Among them, with the high estrate of detecting Acinetobacter baumannii of 51.5% (34/66). After treatment with polymyxin B, the results showed that the clearance rate of microorganisms was 65.2% (43/66), the overall effective rate was 59.0% (23/39), and the 28-day all-cause mortality was 41.0% (16/39). There were no significant differences in clinical efficacy and microbial clearance among patients with different treatment groups of polymyxin B [< 10 days, 10-15 days, and > 15 days groups: effective rates were 56.5% (13/23), 54.5% (6/11), 80.0% (4/5), χ2 = 0.999, P = 0.728; the microbial clearance rates were 43.5% (10/23), 54.5% (6/11), and 80.0% (4/5), χ2 = 2.141, P = 0.393]. The effective and microbial clearance rates of the polymyxin B daily doses of 150 mg and 200 mg groups were significantly higher than those of the daily dose of 100 mg [effectiveness: 85.7% (6/7), 87.5% (7/8) vs. 41.7% (10/24); microbial clearance rate: 71.4% (5/7), 87.5% (7/8) vs. 33.3% (8/24), all P < 0.05], however, there were no significant differences in the length of intensive care unit (ICU) stay and mechanical ventilation time among different daily dose groups. The APACHEⅡscore after polymyxin B administration was significantly lower than before administration (all patients: 16.20±9.24 vs. 24.40±4.73, effective patients: 11.30±4.08 vs. 23.00±4.56, both P < 0.05). Four patients with renal injury had an increase in serum creatinine during the administration of polymyxin B, and recovered after discontinuation of the drug without other adverse reactions. Conclusion:Polymyxin B can be used as an effective treatment option for patients with severe infection of XDR Gram-negative bacteria.

Objective:To develop a deep learning model for predicting three-dimensional (3D) voxel-wise dose distributions for intensity-modulated radiotherapy (IMRT).Methods:A total of 110 postoperative rectal cancer cases treated by IMRT were considered in the study, of which 90 cases were randomly selected as the training-validating set and the remaining as the testing set. A 3D deep learning model named 3D U-Res-Net was constructed to predict 3D dose distributions. Three types of 3D matrices from CT images, structure sets and beam configurations were fed into the independent input channel, respectively, and the 3D matrix of IMRT dose distributions was taken as the output to train the 3D model. The obtained 3D model was used to predict new 3D dose distributions. The predicted accuracy was evaluated in two aspects: the average dose prediction bias and mean absolute errors (MAEs)of all voxels within the body, the dice similarity coefficients (DSCs), Hausdorff distance(HD 95) and mean surface distance (MSD) of different isodose surfaces were used to address the spatial correspondence between predicted and clinical delivered 3D dose distributions; the dosimetric index (DI) including homogeneity index, conformity index, V50, V45 for PTV and OARs between predicted and clinical truth were statistically analyzed with the paired-samples t test. Results:For the 20 testing cases, the average prediction bias ranged from -2.12% to 2.88%, and the MAEs varied from 2.55% to 5.75%. The DSCs value was above 0.9 for all isodose surfaces, the average MSD ranged from 0.21 cm to 0.45 cm, and the average HD 95 varied from 0.61 cm to 1.54 cm. There was no statistically significant difference for all DIs, except for bladder Dmean. Conclusions:This study developed a deep learning model based on 3D U-Res-Net by considering beam configurations input and achieved an accurate 3D voxel-wise dose prediction for rectal cancer treated by IMRT.

Objective To evaluate the feasibility of utilizing dose-volume histogram (DVH) prediction models of organs at risk (OARs) to deliver automatic treatment planning of prostate cancer.Methods The training set included 30 cases randomly selected from a database of 42 cases of prostate cancer receiving treatment planning.The bladder and rectum were divided into sub-volumes (Ai) of 3 mm in layer thickness according to the spatial distance from the boundary of planning target volume (PTV).A skewed normal Gaussian function was adopted to fit the differential DVH of Ai,and a precise mathematical model was built after optimization.Using the embedded C++ subroutine of Pinnacle scripa,ahe volume of each Ai of the remaining validation set for 12 patients was obtained to predict the DVH parameters of these OARa,ahich were used as the objective functions to create personalized Pinnacle script.Finalla,automatic plans were generated using the script.The dosimetric differences among the original clinical plannina,aredicted value and the automatic treatment planning were statistically compared with paired t-test.Results DVH residual analysis demonstrated that predictive volume fraction of the bladder and rectum above 6 000 cGy were lower than those of the original clinical planning.The automatic treatment planning significantly reduced the V70,V60,V50 of the bladder and the V70 and V60 of the rectum than the original clinical planning (all P＜0.05),the coverage and conformal index (CI) of PTV remained unchangea,and the homogeneity index (HI) was slightly decreased with no statistical significance (P＞ 0.05).Conclusion The automatic treatment planning of the prostate cancer based on the DVH prediction models can reduce the irradiation dose of OARs and improve the treatment planning efficiency.